Gamma Delta T cell and keratinocyte cross-talk in diabetic wounds

糖尿病伤口中的 Gamma Delta T 细胞和角质形成细胞的相互作用

• 批准号: 7014442
• 负责人: JULIE M JAMESON
• 金额: $ 23.24万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7014442
• 关键词: T lymphocyte; biological signal transduction; cell cell interaction; cellular pathology; dendritic cells; diabetes mellitus; insulinlike growth factor; keratinocyte; laboratory mouse; medical complication; pathologic process; wound healing

DESCRIPTION (provided by applicant): Dendritic epidermal T cells (DETC) reside in murine skin where they monitor epithelial cells for damage. DETC express a monoclonal gamma-delta T cell receptor (TCR) which is used to recognize an unknown antigen expressed by damaged or stressed keratinocytes. We have previously shown that DETC play roles in skin homeostasis and wound repair via the production of insulin-like growth factor-1 (IGF-1) and keratinocyte growth factors (KGFs). Work in diabetic mice and humans indicate that diminished levels of IGF-1 and KGFs at the wound site contribute to impaired wound repair. We hypothesize that impaired growth factor production and defective proliferation of keratinocytes in the diabetic wound are the result of DETC dysfunction. Initially we will determine whether DETC are functional in diabetic wounds by examining DETC activation, proliferation, and growth factor production. In addition we will investigate which mechanisms may contribute to DETC dysfunction in diabetes including: changes in insulin receptor (IR) signaling, inhibition by glucocorticoids, and decreased IGF-1 receptor (IGF-1 R) signaling. By developing an understanding of DETC-keratinocyte cross-talk during wound healing in diabetic mice we may uncover new mechanisms that can be exploited to increase the efficiency of wound repair and provide insight into the timing of IR and IGF-1 R signaling. The proposed experiments are exploratory in nature and involve type I and type II diabetic mouse models of wound repair. Diabetic non-healing wounds are a debilitating complication and treatment is a considerable burden to health services. Results from this proposal may lead to new directions aimed at targeting DETC for future therapies and studying intra-epithelial gamma-delta T cells in other tissues affected by diabetes such as the gut.

描述（由申请人提供）：树突状表皮T细胞（DETC）居住在鼠皮肤中，在那里它们监测上皮细胞是否损坏。 DETC表达单克隆伽马 - 戴尔塔T细胞受体（TCR），用于识别由受损或压力的角质形成细胞表达的未知抗原。我们先前已经表明，通过产生胰岛素样生长因子1（IGF-1）和角质形成细胞生长因子（kGFS），开发物在皮肤稳态和伤口修复中起作用。在糖尿病小鼠和人类中的工作表明，伤口部位的IGF-1和KGF水平降低会导致伤口修复受损。我们假设糖尿病伤口中角质形成细胞的生长因子的产生受损和疾病的不良增殖是DETC功能障碍的结果。最初，我们将通过检查DETC激活，增殖和生长因子的产生来确定DETC是否在糖尿病伤口中起作用。此外，我们将研究哪些机制可能导致糖尿病的发病功能障碍，包括：胰岛素受体信号（IR）信号的变化，糖皮质激素抑制以及IGF-1受体（IGF-1 R）信号降低。通过在糖尿病小鼠伤口愈合过程中对DETC-KERATINOCYTE串扰的理解，我们可能会发现可以利用的新机制来提高伤口修复的效率，并可以深入了解IR和IGF-1 R信号的时机。提出的实验本质上是探索性的，涉及I型和II型糖尿病小鼠伤口修复模型。糖尿病非愈合伤口是一种使人衰弱的并发症，治疗是卫生服务的巨大负担。该提案的结果可能导致旨在针对未来疗法的鉴定并研究其他受糖尿病（例如肠道）的组织中的上皮内伽马 - 戴尔塔T细胞的新方向。